68% of US adults are either overweight or obese, and more than 100 million Americans have diabetes or pre- diabetes. These conditions may lead to cardiovascular disease and cancer. Recent research indicates a potential role for polychlorinated biphenyls (PCBs), which are persistent organic pollutants in obesity and diabetes. PCBs were previously used in electrical transformers. Although they were banned over 30 years ago, PCBs are still present in the US food supply and in all adult Americans. Preliminary research performed by our group and others suggests that PCBs cause a leaky gut to disrupt the gut:liver:adipose axis. Subsequently, intestinal-derived bacterial products enter the bloodstream causing inflammation, liver disease and contribute to obesity and diabetes. We call this problem toxic-metabolic endotoxemia. We hypothesize that PCBs interact with high fat or high carbohydrate diets through toxic metabolic endotoxemia to worsen obesity and diabetes; and studying this hypothesis is the overall objective of this grant. The specific aims of this novel nutrient:toxin interaction translational project are to: 1) Determine in mice, mechanisms by which PCBs disrupt the gut:liver:adipose axis to increase metabolic endotoxemia and worsen diet-induced obesity/insulin resistance. 2) Determine the potential role of cellular receptors in PCBs-associated toxic-metabolic endotoxemia in mice and cell culture models. 3) Study mechanisms of toxic metabolic endotoxemia in stored blood samples from a large group of highly PCB-exposed humans. We expect to find that PCBs activate receptors, perturb the gut:liver:adipose axis, and worsen obesity/diabetes via toxic metabolic endotoxemia in mice and in humans. This innovative project is the first to study PCB- related endotoxemia in obesity/diabetes and is expected to lead to a new understanding of these conditions. The proposal is relevant to all overweight/obese people exposed to environmental pollution.